Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis

Background Methylxanthine, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear recommendations or guidelines on how to choose between caffeine and aminophylline. Objective This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for apnea of prematurity, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity. Methods PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022. Results Ten studies including a total of 923 preterm infants were evaluated. Our results showed that there was no significant difference in the effective rate of 1-3days between caffeine and aminophylline (OR 1.05, 95%CI: 0.40–2.74, P = 0.914). However, for side effects such as tachycardia (OR 0.22, 95%CI: 0.13–0.37, P<0.001) and feeding intolerance (OR 0.40, 95%CI: 0.23–0.70, P = 0.001), the incidence rate was lower in the caffeine group compared with the aminophylline group. No significant difference was found in hyperglycemia (OR 0.45, 95%CI: 0.19–1.05, P = 0.064). Conclusion This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment.


Inclusion and exclusion criteria
In this meta-analysis, the research needed to meet the following inclusion criteria: 1. Infants born <37 weeks of gestation and diagnosed with apnea (Respiratory arrest for �20 s, may be accompanied by bradycardia (heart rate <100 bpm) or oxygen desaturation (SpO 2 <80%), and that occurred more than 12 h after birth.); 2. Randomized controlled studies and observational studies; 3. A group exposed to caffeine citrate therapy (exposure group), a group exposed to aminophylline therapy (control group), and there was a comparison among the two groups; 4. At least one of the parameters was included in the outcome measures: the effective rate of 1-3days, sinus tachycardia, feeding intolerance, hyperglycemia, total adverse effects. The effective of 1-3days was defined as 50% or greater reduction in apnea episodes within 72h and <3 times/day after administrating the drugs [14]; Sinus tachycardia is defined as the heart rate persistence >160 bpm or the heart rate > 20% of the baseline heart rate after medication in infants. The diagnosis of feeding intolerance and hyperglycemia relies on the documentation of medical or surgical data.
In this meta-analysis, any of the following literature that met the exclusion criteria were excluded: 1. Reviews, case reports, meeting abstracts, animal trials, or trial registration reports; 2. Full text was unavailable; 3. Unclear or inappropriate definition of exposure/results; 4. Limited information was available for extracting or duplicating data.

Data extraction
Two researchers reviewed each study independently according to the inclusion and exclusion criteria, any ambiguities were reviewed by a third researcher. First, we eliminated duplicate files, filtered the studies by titles and abstracts, and then read the full-text details to filter irrelevant studies. The two researchers recorded with excel spreadsheets and independently extracted data from articles that met the requirements. The specific format is as follows: (1) General characteristics of study: study, year, study type. (2) Intervention: gestation age, the number of participants, dosage. (3) Outcomes.
controlled trials, including randomized evaluation, blind method of outcome evaluation and description of withdrawal and dropouts. A study with a Jadad score of more than 3 was considered to be of high quality.

Statistical analysis
In our study, STATA software version 12.0 (Stata Corp, College Station, TX) was used for analysis. For continuous results, MD and 95% confidence intervals (CI) were used for calculations. For dichotomous results, OR and 95% CI were used for calculations. Heterogeneity was evaluated by I 2 statistics. When I 2 <50%, no heterogeneity was considered to exist. When I 2 �50%, a great heterogeneity was considered. Funnel plot, Begg's and Egger's tests were performed to evaluate publication bias. To evaluate the stability of the results, sensitivity analysis of ignoring one study at a time was carried out. P <0.05 was considered to be statistically significant.

Search results
A total of 408 studies were initially screened by the research team, with 373 remaining after duplicate publications were eliminated by computer. Then, 326 studies were excluded by screening titles and abstracts. Finally, two randomized controlled trials and eight observational studies were considered eligible for inclusion [15][16][17][18][19][20][21][22][23][24]. The flowchart depicts the selection procedure for the ten studies (Fig 1). Table 1 demonstrates the characteristics of the included studies.
S3 Table shows the details of the NOS quality assessment. From the Newcastle-Ottawa scale, the quality of the included cohort studies ranged from 7 to 9, indicating that the quality of the studies was fair. The quality of the 2 randomized controlled trials we included was at an intermediate level.

Meta analysis results
The effective rate of 1-3days. The effective rate of 1-3days was included as an outcome of 5 studies which involved 365 infants. No significant difference was observed between the caffeine group and the aminophylline group regarding the effective rate of 1-3days (OR 1.05, 95% CI: 0.40-2.74, P = 0.914). There was significant heterogeneity between these studies, so we performed the randomed-effect model in our study (I 2 = 51.6%, P = 0.083, Fig 2).
Tachycardia. Tachycardia was included as an outcome between caffeine citrate and aminophylline in 6 studies which involved 557 preterm infants. In the meta-analysis, we observed that the caffeine group had lower incidence of tachycardia compared with the aminophylline group (OR 0.22, 95%CI: 0.13-0.37, P<0.001). There was no significant heterogeneity among these studies (I 2 = 0.0%, P = 0.588, Fig 3). Thus we conducted the meta-analysis using a fixedeffect model.
Feeding intolerance. A total of 4 studies (363 infants) recorded the number of infants with feeding intolerance in the caffeine group and the aminophylline group. Compared with aminophylline, preterm infants treated with caffeine citrate had a lower probability of feeding intolerance (OR 0.40, 95%CI: 0.23-0.70, P = 0.001). Heterogeneity among studies was low (I 2 = 38.6%, P = 0.181, Fig 4).
Hyperglycemia. Hyperglycemia was included as an outcome between caffeine citrate and aminophylline in 3 studies which involved 343 preterm infants. There was no significant heterogeneity between these studies (I 2 = 0.0%, P = 0.617, Fig 5). However, there was no significant difference between the caffeine citrate and aminophylline groups in terms of hyperglycemia (OR 0.45, 95%CI: 0.19-1.05, P = 0.064).
Total adverse effects. Total adverse effects was included as an outcome between caffeine citrate and aminophylline in 4 studies which involved 128 preterm infants. The analysis found that compared with aminophylline, infants in the caffeine group had a lower chance of developing total adverse effects (OR 0.41, 95%CI: 0.17-0.97, P = 0.042). And the heterogeneity among studies was low (I 2 = 22.4%, P = 0.276, Fig 6).

Sensitivity and publication bias analysis
Sensitivity analysis of each indicator showed that the results were reliable and stable. Publication bias was calculated using the funnel plot, and there was no obvious asymmetry. Moreover, no obvious publication bias was detected by Begg's and Egger's tests (P > 0.05).

Discussion
Although methylxanthine has been widely administered in many countries for the treatment of AOP, the choice between caffeine and aminophylline is still controversial. It is well known that caffeine has a wider effectiveness as well as less adverse effects than aminophylline, and does not require routine blood concentration measurements [25]. But the present findings reported that there is no difference between caffeine and aminophylline in terms of incidence apneic, bradycardic or hypoxemic [26]. What's more, aminophylline is effective in improving the renal function of asphyxiated neonates [27]. Therefore, our meta-analyses aimed to assess the comparative efficacy and safety of caffeine and aminophylline in the treatment of AOP. The results indicated that caffeine was as effective as aminophylline in terms of treating AOP, the occurrence of tachycardia and feeding intolerance in the caffeine group was clearly less than that in the aminophylline group. But the rates of hyperglycemia were similar between the caffeine and aminophylline groups. the loading dose of 6.2mg/kg followed by a maintenance dose of 3.1 mg/kg iv or by a gastric baby feeding tube twice a day for 10 days.  We believe that caffeine and aminophylline treatments are equivalent effective in reducing apnea of prematurity, which has been confirmed in several independent studies [28,29]. Steer similarly concluded that in the short term, caffeine was as effective as aminophylline in reducing the incidence of apnea and was better tolerated and easier to administer. These are related to the mechanism of methylxanthine, caffeine and aminophylline are both central nervous  system stimulants. They have the same effect of increasing diaphragm contractility and lowering hypercapnia susceptibility threshold [30]. Some studies have further shown that prophylactic use of caffeine for preterm infants at risk of apnea reduced the duration of mechanical ventilation [31]. Borszewska-Kornacka [32] found that preventive use of caffeine within 24 hours after birth can reduce the use of invasive ventilator and the incidence of IVH and PDA compared with therapeutic use of caffeine. However, whether caffeine should be used  prophylactically in all preterm infants remains controversial [33]. It is necessary to conduct a definitive study to illustrate the comparative effects of prophylactic and therapeutic caffeine.
Tachycardia is one of the most common acute adverse reactions of methylxanthines. We demonstrated a lower incidence of tachycardia in infants treated with caffeine compared with aminophylline. Our result is consistent with those obtained by Alhersh et al. [34]. One possible interpretation of the result is that caffeine is more active than aminophylline in stimulating central nervous system, but less active in stimulating heart [35]. In addition, aminophylline contains phenethyl alcohol, which could directly stimulate the respiratory center to increase its sensitivity to carbon dioxide, leading to an increase in respiratory rate, thus causing tachycardia in preterm infants. Ultimately, aminophylline exhibits unique toxicokinetics in premature infants with sinus tachycardia due to the great developmental differences between neonates and adults [36]. As a result, caffeine is superior to aminophylline in terms of the risk of tachycardia.
Our study showed that caffeine significantly reduced the incidence of feeding intolerance compared with aminophylline treatment, the result is indeed in line with research of Rostas et al. [4]. Analyzing the possible causes, the serum half-life of aminophylline ranges from 24.7 to 36.5 h, while caffeine's serum half-life is 101 h in preterm infants [18]. Caffeine has a longer elimination half-life, allowing for once-daily dosing. Therefore, administration once a day has less effect on the upper gastrointestinal tract than administration multiple times a day. Another reason could be that caffeine is absorbed more rapidly by gastrointestinal tract than aminophylline, with little or no first-pass metabolism [37]. In addition, the dosage of caffeine therapy can be challenging because of the limited hepatic, renal, and respiratory function of preterm infants. A previous study has shown that high doses of caffeine lead to the decrease of mesenteric blood flow and serious feeding intolerance of caffeine generally appears at concentrations >60 mg/L [30]. But chen [38] found that higher doses of caffeine (10-20 mg/kg daily) were more effective than lower doses (5-10 mg/kg daily) and that higher doses were more closely associated with withdrawal from the ventilator. Definitive recommendations on the optimal caffeine dose cannot be given due to our research not making a specific distinction between drug doses, future research is necessary to elucidate the effects of different maintenance doses of caffeine in the treatment of AOP.
Furthermore, our study shows the risk of hyperglycemia of caffeine is similar to that of aminophylline. Our results are different from those of Hady et al., who found caffeine has little risk of hyperglycemia, which is associated with its hydrophobicity and distributes rapidly without tissue accumulation [35]. The discrepancy between our study and others may be due to the insufficient number of studies we included on measures of hyperglycemia. More well-designed and larger sample studies should be carried out to examine and expand the conclusions.
Some literature did not describe specific types of adverse reactions, but summarized all the adverse reactions in general, so we further discussed the risk of total adverse effects. The results of our meta-analysis indicated that the total adverse effects rate of caffeine in the treatment of apnea is lower than that of aminophylline. It may be related to the narrow safe range of aminophylline concentration in blood. Ye [39] have also suggested that excessive serum concentration of aminophylline was related to an increased risk of adverse effects. Patients with aminophylline blood concentration >20 μg/ml may have symptoms such as tachycardia and arrhythmia, while patients with aminophylline blood concentration >40 μg/ml may have symptoms such as fever, dehydration, convulsion and even death. However, caffeine has a wide range of safety, with serum levels of 3-84 mg/L considered therapeutic and safe [40]. Furthermore, the plasma concentration fluctuation of caffeine in neonates is smaller than aminophylline, caffeine has greater central nervous system penetration, and does not produce fluctuation of cerebral blood flow [41]. Liu et al. [42] has shown that caffeine may have a direct long-term neuroprotective effect on the developing brain. Mürner-Lavanchy et al. [43] also reported that caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine. In order to truly prove the safety of caffeine citrate, more longterm follow-up studies are necessary.
Our meta-analysis differs from other analyses in that it not only compares the effectiveness of caffeine and aminophylline, but also evaluates their safety in preterm infants. Despite the overwhelming evidence that caffeine is safer and more effective than aminophylline, and the resulting widespread use in developed countries. However, the use of caffeine therapy remains alarmingly low in sub-Saharan Africa, greater efforts are needed to ensure broader utilization of caffeine therapeutic regimens.

Limitation
It is worth noting that our meta-analysis still has many limitations. First, limited number of RCTs were retrieved, and we included relevant non-RCT studies to expand the total sample size. The limited number of RCTs resulted in a smaller randomized sample size, which may have biased the results. Moreover, the information on long-term outcomes of methylxanthines in our included studies is still insufficient and large-scale trials should be conducted in the future to evaluate the potential long-term adverse outcomes in clinical practice.

Conclusion
In summary, evidence has shown that caffeine and aminophylline are equally effective for apnea of prematurity but caffeine has fewer adverse effects on infants. For these reasons, we recommend caffeine as an effective and feasible first-line treatment for apnea in preterm infants. We believe it will help update the available evidence on the benefits and harms of methylxanthine treatment for AOP, thus enabling researchers and clinicians to make the proper choice for the treatment of AOP.
Supporting information S1